Identifying gene-gene interactions or gene-environment interactions in studies of human complex diseases remains a big challenge in genetic epidemiology. An additional challenge, often forgotten, is to ... [more ▼]

Identifying gene-gene interactions or gene-environment interactions in studies of human complex diseases remains a big challenge in genetic epidemiology. An additional challenge, often forgotten, is to account for important lower-order genetic effects. These may hamper the identification of genuine epistasis. If lower-order genetic effects contribute to the genetic variance of a trait, identified statistical interactions may simply be due to a signal boost of these effects. In this study, we restrict attention to quantitative traits and bi-allelic SNPs as genetic markers. Moreover, our interaction study focuses on 2- way SNP-SNP interactions. Via simulations, we assess the performance of different corrective measures for lower-order genetic effects in Model-Based Multifactor Dimensionality Reduction epistasis detection, using additive and co-dominant coding schemes. Performance is evaluated in terms of power and familywise error rate. Our simulations indicate that empirical power estimates are reduced with correction of lower-order effects, likewise familywise error rates. Easy-to-use automatic SNP selection procedures, SNP selection based on ‘‘top’’ findings, or SNP selection based on p-value criterion for interesting main effects result in reduced power but also almost zero false positive rates. Always accounting for main effects in the SNP-SNP pair under investigation during Model-Based Multifactor Dimensionality Reduction analysis adequately controls false positive epistasis findings. This is particularly true when adopting a co-dominant corrective coding scheme. In conclusion, automatic search procedures to identify lower-order effects to correct for during epistasis screening should be avoided. The same is true for procedures that adjust for lower-order effects prior to Model-Based Multifactor Dimensionality Reduction and involve using residuals as the new trait. We advocate using ‘‘on-the-fly’’ lower-order effects adjusting when screening for SNP-SNP interactions using Model-Based Multifactor Dimensionality Reduction analysis. [less ▲]

Background: The role of IgE in patients with severe asthma is not fully understood. Objective: We sought to investigate whether IgE to Staphylococcus aureus enterotoxins might be relevant to disease ... [more ▼]

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown exponentially over the last few years. It has been marked by promising methodological developments ... [more ▼]

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown exponentially over the last few years. It has been marked by promising methodological developments, improved translation efforts of statistical epistasis to biological epistasis and attempts to integrate different omics information sources into the epistasis screening to enhance power. The quest for gene-gene interactions poses severe multiple-testing problems. In this context, the maxT algorithm is one technique to control the false-positive rate. However, the memory needed by this algorithm rises linearly with the amount of hypothesis tests. In main-effects detection, this is not a problem since the memory required is thus proportional to the number of SNPs. In contrast, gene-gene interaction studies will require a memory proportional to the squared amount of SNPs. A genome wide epistasis would therefore require terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. Methods: In this work we present a new version of maxT, requiring an amount of memory independent from the number of genetic effects to be investigated. This algorithm was implemented in C++ in our epistasis screening software MB-MDR-2.6.2 and compared to MB-MDR's first implementation as an R-package (Calle et al., Bioinformatics 2010). We evaluate the new implementation in terms of memory efficiency and speed using simulated data. The software is illustrated on real-life data for Crohn's disease. Results: The sequential version of MBMDR-2.6.2 is approximately 5,500 times faster than its R counterparts. The parallel version (tested on a cluster composed of 14 blades, containing each 4 quad-cores Intel Xeon CPU E5520@2.27 GHz) is approximately 900,000 times faster than the latter, for results of the same quality on the simulated data. It analyses all gene-gene interactions of a dataset of 100,000 SNPs typed on 1000 individuals within 4 days. Our program found 14 SNP-SNP interactions with a p-value less than 0.05 on the real-life Crohn’s disease data. Conclusions: Our software is able to solve large-scale SNP-SNP interactions problems within a few days, without using much memory. A new implementation to reach genome wide epistasis screening is under construction. In the context of Crohn's disease, MBMDR-2.6.2 found signal in regions well known in the field and our results could be explained from a biological point of view. This demonstrates the power of our software to find relevant phenotype-genotype associations. [less ▲]

It is generally believed that epistasis makes an important contribution to the genetic architecture of complex disease, and numerous statistical and bioinformatics methods have been developed to detect it ... [more ▼]

BACKGROUND: Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE: We sought ... [more ▼]

BACKGROUND: Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE: We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. METHODS: Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. RESULTS: Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. CONCLUSION: Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis. [less ▲]

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model ... [more ▼]

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information. [less ▲]

To cite this article: Mahachie John JM, Baurecht H, Rodriguez E, Naumann A, Wagenpfeil S, Klopp N, Mempel M, Novak N, Bieber T, Wichmann H-E, Ring J, Illig T, Cattaert T, Van Steen K, Weidinger S. Analysis of the high-affinity IgE receptor genes reveals epistatic effects of FCER1A variants on total IgE levels and eczema risk. Allergy 2009; DOI: 10.1111/j.1398-9995.2009.02297.x. Abstract Background: High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema. Methods: We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls. Results: Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected. Conclusions: These results suggest that FCER1A variants by themselves and in combination influence IgE levels and act synergistically to influence eczema risk. [less ▲]

Space plasmas are often observed to contain more particles in the high-energy tail than the usual Maxwellian distributions, and are well modeled by kappa distributions. The hybrid kappa-Maxwellian ... [more ▼]

Space plasmas are often observed to contain more particles in the high-energy tail than the usual Maxwellian distributions, and are well modeled by kappa distributions. The hybrid kappa-Maxwellian distribution and associated generalized plasma dispersion function Z(kappa M) were recently introduced to model magnetized space plasmas. The susceptibility tensor for a kappa-Maxwellian plasma component is derived, making use of Z(kappa M). This enables one to make general studies of obliquely propagating electromagnetic waves in a magnetoplasma. The susceptibility and dielectric tensors reduce to the Maxwellian expressions in the limit kappa ->infinity. As an illustration, the formalism is applied to the lower branch of the R mode and its off-parallel variant. For low kappa values, low-wavenumber, low-frequency parallel whistler waves are shown to be stable, unlike the Maxwellian case, which is unstable if the perpendicular temperature exceeds the parallel temperature. A numerical study is made of the effects of the value of kappa, the propagation angle, and the temperature anisotropy ratio on dispersion and damping. The kappa-Maxwellian distribution with very low kappa is found to be unstable in an overdense plasma near the electron-cyclotron frequency even when the parallel and perpendicular temperatures are equal, because of the anisotropy of the contours in velocity space. (C) 2007 American Institute of Physics. [less ▲]

Earlier Sagdeev pseudopotential treatments of ion-acoustic double layers in plasmas with two electron populations were based on a model in which both electron densities were described by isothermal ... [more ▼]

Earlier Sagdeev pseudopotential treatments of ion-acoustic double layers in plasmas with two electron populations were based on a model in which both electron densities were described by isothermal Boltzmann distributions. Using a more recent fluid-dynamical approach, with polytropic equations of state indices gamma(j), one finds analytically that no double layers can be formed for gamma(j)>= 3/2, due to total rarefaction of the cooler electrons or infinite compression of the ions. For gamma(j)< 3/2, rarefactive double layers occur, but, just below 3/2, at unrealistically small cool electron densities or large Mach numbers. As gamma(j) decreases towards 1, these constraints become less restrictive and go over smoothly to those known from Boltzmann studies. Contrary to what appears in the literature, very weak compressive double layers can also be found for Boltzmann electrons, but only for soliton conditions barely above the existence threshold; i.e., marginally super-ion-acoustic. Any slight increase in the critical Mach number destroys the possibility of having positive double layers, and, within the limits of numerical accuracy, no window could be found for gamma(j)not equal 1, where compressive double layers exist.(c) 2006 American Institute of Physics. [less ▲]

in Journal of Physics : A Mathematical & General (2006), 39(12), 3137-3146

The existence domains for one-dimensional acoustic solitons and double layers in complex (dusty) plasmas with two ion temperatures are obtained, using the fluid dynamic paradigm with a general polytropic ... [more ▼]

The existence domains for one-dimensional acoustic solitons and double layers in complex (dusty) plasmas with two ion temperatures are obtained, using the fluid dynamic paradigm with a general polytropic equation of state. Dust-acoustic solitons are considered in a four-component plasma of negative dust grains, cool and very hot ions, and very hot electrons. Whereas in a dust-ion-electron plasma only negative potential solitons are supported, the presence of a second ion component allows positive potential solitons to occur as well. The existence domain in parameter space is delineated, in particular, also for the reduced three-component case in which there are no free electrons, all electrons being adsorbed onto the dust grains. Next, the ion-acoustic regime is considered. Both positive and negative potential dust-ion acoustic solitons and double layers are found, and their existence conditions in the parameter space of cool ion density and Mach number derived. [less ▲]

Molecular clouds are self-gravitating fluids that support different waves and contain highly nonlinear clumps and filaments, for which explanations have been sought in terms of solitons. The present paper ... [more ▼]

Molecular clouds are self-gravitating fluids that support different waves and contain highly nonlinear clumps and filaments, for which explanations have been sought in terms of solitons. The present paper explores the possibility that several ( neutral) species with different thermal speeds coexist, as in a molecular cloud consisting of gas and dust, or of a mixture of normal matter and dark matter. It is shown that this model can support soliton formation, both with humps or dips in the self-gravitational potential. The existence domain has been given in terms of the hot species Mach number and fractional mass density, in a gas-dynamic description which emphasizes the constraints coming from the sonic and neutral points, and from the limits due to infinite compression or total rarefaction. One species is compressed while the other is rarefied, allowing the system to reach a mass neutral point outside equilibrium. In this way, solitons are possible without invoking interaction with a weakly ionized cloud component or involving envelope solitons that are not really stationary structures. [less ▲]

Distributions with excess numbers of superthermal particles are common in space environments. They are well modelled by the isotropic kappa distribution, or, where magnetic effects are important, the ... [more ▼]

Distributions with excess numbers of superthermal particles are common in space environments. They are well modelled by the isotropic kappa distribution, or, where magnetic effects are important, the kappa-Maxwellian. This paper presents a review of some studies of electrostatic and electromagnetic waves in such plasmas, based on the associated generalized plasma dispersion functions, Z(kappa) and Z(kappa M). In particular, the effects of low values of kappa are considered, i.e. strongly accelerated distribution functions. Recently the full susceptibility tensor for oblique propagation of electromagnetic waves in a kappa-Maxwellian magnetoplasma has been established and has been applied to the study of whistler waves. [less ▲]

An overview is given of methods to study weak and strong nonlinear modes in multispecies plasmas, with a discussion of how they correspond (or not) for phenomena at not too strong amplitudes. Reductive ... [more ▼]

An overview is given of methods to study weak and strong nonlinear modes in multispecies plasmas, with a discussion of how they correspond (or not) for phenomena at not too strong amplitudes. Reductive perturbation analysis leads for weak nonlinear waves to several well known nonlinear evolution equations. In contrast, strong nonlinear phenomena are dealt with by immediately looking for stationary solutions of the model equations. While this works well for electrostatic modes via the Sagdeev pseudopotential technique, large amplitude, parallel propagating solitary electromagnetic waves occur as oscillitons, for which the correct nonlinear evolution equation is still lacking. Electromagnetic modes in (relativistic) electron-positron plasmas are an exception, in that they give pure solitons, both at large and smaller nonlinear amplitudes. The behaviour of the wave magnetic field is expressed through an energy integral that involves the Mach number of the structure, thus yielding the limits on the allowable Mach numbers and soliton amplitudes. [less ▲]

The usual description of dust-modified ion-acoustic and dust-acoustic solitons in plasmas containing negative dust is in terms of Boltzmann distributions for the hotter species. In the dust-modified ion ... [more ▼]

The usual description of dust-modified ion-acoustic and dust-acoustic solitons in plasmas containing negative dust is in terms of Boltzmann distributions for the hotter species. In the dust-modified ion-acoustic regime, besides positive potential solitons, negative structures can also be generated, for electrons with a polytropic index gamma(e)not equal 1, as well as for Boltzmann electrons, subject to conditions that are not too stringent. These general conditions were previously either ignored or given for weakly nonlinear solutions only. In the dust-acoustic domain in plasmas with negatively charged dust, however, only negative potential solitons can occur, even when the lighter species have non-Boltzmann distributions. For Boltzmann electrons only an infinite dust compression limits the soliton amplitudes and corresponding Mach numbers, whereas for gamma(e)not equal 1, the electron density, too, can be a limiting factor for the existence domain of such solitons. (c) 2005 American Institute of Physics. [less ▲]

Using the fluid dynamic paradigm, we study acoustic solitons in a dusty plasma with two ion temperatures, using a polytropic equation of state. On the ion-acoustic timescale we consider a four-component ... [more ▼]

Using the fluid dynamic paradigm, we study acoustic solitons in a dusty plasma with two ion temperatures, using a polytropic equation of state. On the ion-acoustic timescale we consider a four-component plasma, with super-hot electrons and massive dust grains. We find existence regimes for both positive and negative potential solitons and double layers. For dust-acoustic solitons, we consider a three-component plasma, with no free electrons, and "super-hot" hot ions. This model supports both positive and negative potential solitons, unlike a dust-ion-electron plasma, that allows only negative solitons [less ▲]